Current anti-cancer drugs based on platinum (cisplatin (i.e., cis-[PtCl2(NH3)2], cis-DDP); carboplatin (i.e., cis-[Pt(CBDCA)(NH3)2], (CBDCA=cyclobutane-1,1-dicarboxylate)); and oxaliplatin (i.e., [Pt(ox)(dach)] (dach=1,2-diaminocyclohexane, ox=oxalato)) share similar clinical properties due to their structural similarities (namely, their cis geometry around the platinum atom). Their mechanisms of action, especially with respect to the purported target DNA, are also consequently very similar. While these are the drugs of choice for the treatment of many types of tumors, with time, tumor cells develop resistance to their cytotoxic effects. The hope in the search for new platinum-based drugs with novel pharmacological properties lies in finding structurally new compounds with fundamentally different mechanisms of action. Such drugs would be useful both on a stand-alone basis for cancer therapy, and would be of particular interest for treating tumors that have become resistant to traditional Pt-based drugs.
For a long time, it was widely believed that, to be cytotoxic and antitumor active, a platinum drug must have a cis geometry with general formula cis-[PtX2(am(m)ine)2] where X is considered the leaving group, usually chloride or X2 is a bidentate carboxylate such as 1,1-cyclobutanedicarboxylate (CBDCA) or oxalate. The am(m)ine is the donor ligand and is often NH3 or (amine)2 can be a bidentate amine such as 1,2-diaminocyclohexane. The three clinically approved drugs in the United States—cisplatin, carboplatin and oxaliplatin—are all covered by this general formula.
One approach to expand the anticancer spectrum of platinum agents has been to examine structurally unique platinum agents. Through this approach, polynuclear platinum compounds (e.g., trinuclear BBR3464) have emerged as a class. (Farrell, N: Polynuclear Drugs. Metal Ions in Biol. Sys. 41:252-296 (2004); Farrell, N.: Platinum Anti-cancer drugs. From Laboratory to Clinic. ACS Symposium Series 903 “Medicinal Inorganic Chemistry,” Sessler, J. A., Doctorow, S. E., McMurry, T. J. and Lippard, S. J. Eds., 62-79 (2005).
Another approach has been to explore the trans geometry. Farrell, N., Current status of structure-activity relationships of platinum anti-cancer drugs: activation of the trans geometry, Met. Ions Biol. Syst., 1996, 32, 251-296; Intini, F. P.; Boccarelli, A.; Francia, V. C.; Pacifico, C. Sivo, M. F.; Natile, G.; Giordano, D.; Rinaldis, P.; Coluccia, M., Platinum complexes with imino ethers or cyclic ligands mimicking imino ethers: synthesis, in vitro antitumour activity, and DNA interaction properties, J. Biol. Inorg. Chem., 2004, 9, 768-780. The paradigm for the early structure activity relationships (SARs) was that the trans geometry, trans-[PtCl2(NH3)2] (trans-DDP) was therapeutically inactive.
Substitution of the NH3 group by a sterically hindered planar amine trans-[PtCl2(L)(L′)] (L=NH3, L′=pyridine, quinoline, thiazole, etc. and/or L=L′=pyridine or thiazole) gives transplanaramine (TPA) compounds with cytotoxity to cisplatin in human tumor cell-lines. (van Beusichem, M.; Farrell, N., Activation of the trans geometry in platinum antitumor complexes. Synthesis, characterization, and biological activity of complexes with the planar ligands pyridine, N-methylimidazole, thiazole, and quinoline. Crystal and molecular structure of trans-dicholorobis(thiazole)platinum(II), Inorg. Chem. 1992, 31, 634-639; Farrell, N.; Kelland, L. R.; Roberts, J. D.; van Beusichem, M., Activation of the trans geometry in platinum antitumor complexes: a survey of the cytotoxity of trans complexes containing planar ligands in murine L1210 and human tumor panels and studies on their mechanism of action, Cancer Res., 1992, 52, 5056-5072.) Use of the planar amine enhances cytotoxicity up to 100-fold over trans-[PtCl2(NH3)2]. Further, the compounds generally maintain cytotoxicity in cisplatin-resistant lines.
Since those initial reports by Farrell et al., other groups confirmed the effects of a sterically demanding group in modulation of the cytotoxicity of the transplatinum structure—amines used include cyclohexylamine (Mellish, K. J.; Barnard, C. F. J.; Murrer, B. A.; Kelland, L. R., DNA-binding properties of novel cis- and trans-platinum-based anticancer agents in 2 human ovarian carcinoma cell lines, Int. J. Cancer, 1995, 62, 717-723), branched aliphatic amines (Monterro, E. I.; Diaz, S.; Gonzalez-Vadillo, A. M.; Perez, J. M.; Alonso, C., Navarro-Ranninger, C., Preparation and Characterization of Novel trans-[PtCl2(amine)(isopropylamine)] Compounds: Cytotoxic Activity and Apoptosis Induction in ras-Transformed Cells, J. Med. Chem., 1999, 42, 4264-4268), piperzine, piperidine (Khazanov E.; Barenholz Y.; Gibson D.; Najajreh Y., Novel apoptosis-inducing trans-platinum piperidine derivatives: synthesis and biological characterization, J. Med. Chem. 2002, 45, 5196-204; Najajreh Y.; Perez J. M.; Navarro-Ranninger, C.; Gibson, D. Novel soluble cationic trans-diaminedichloroplatinum(II) complexes that are active against cisplatin resistant ovarian cancer cell lines, J. Med. Chem. 2002, 45, 5189-95) and iminoethers (Intini et al., supra). In general the cytotoxicity of these various compounds is in the 1-20 μM range and is characterized by lack of cross-resistance to cisplatin. The DNA binding profiles of these various compounds show a wide diversity in comparison to those of the cisplatin family. The discovery that trans compounds of formula trans-[PtX2(amine)2] or trans-[PtX2 (iminoether)2] can also be cytotoxic has opened a new opportunity in the search of new drugs with cytotoxicity profiles complementary to that of the known clinical agents. Substitution of the NH3 group by a sterically hindered planar amine trans-[PtCl2(L)(L′)] (L=NH3, L′=pyridine, quinoline, thiazole, etc. and/or L=L′=pyridine or thiazole) gives “transplanaramine” (TPA) compounds with cytotoxicity comparable to cisplatin in human tumor cell lines. A study of the cytotoxicity of the trans-[PtCl2(L)(L′)] series across the NCI human tumor cell line panel showed a unique profile and activity in both cisplatin and oxaliplatin-resistant cells (Fojo T, Farrell, N, Ortuzar, W., Tanimura, H., Weinstein, J., and Myers, T. G.: Identification of non-cross-resistant platinum compounds with novel cytoxicity profiles using the NcI anticancer drug screen and clustered image map visualizations. Crit. Revs. Oncol./Hematool. 53:25-34 (2005).) As stated, all modifications of transplatinum compounds reported to date are of the form trans-[PtCl2(L)(L′)] where L and L′ are various amines other than NH3. Unfortunately, these compounds are poorly soluble in aqueous medium and thus their in vivo bioavailability is attenuated. In addition, these known compounds still contain the relatively reactive Cl—Pt—Cl axis, making them unstable in the cellular environment. (McGowan, G.; Parsons, S.; Sadler, P. J., Inorg. Chem., 2005, 44, 7459-7467.)
There is therefore an ongoing need to develop new transplatinum compounds that are effective cytotoxic and antitumor agents. It would be particularly advantageous if the agents were water soluble, stable in the cellular environment, and cytotoxic and antitumor active in tumor cells that develop resistance to other known anti-tumor agents.
The following also are mentioned as background:
U.S. Pat. No. 4,979,393 issued Jan. 10, 1989 to N. Farrell et al., for “Bis-platinum complexes as chemotherapeutic agents.”
U.S. Pat. No. 4,921,963 issued May 1, 1990 to Skov, Farrell, et al., for “Platinum complexes with one radiosensitizing ligand.”
U.S. Pat. No. 5,026,694 issued Jun. 25, 1991 to Skov, Farrell, et al., for “Platinum complexes with one radiosensitizing ligand.”
U.S. Pat. No. 5,028,726 issued Jul. 2, 1991, to Farrell for “Platinum amine sulfoxide complexes.”
U.S. Pat. No. 5,107,007 issued Apr. 21, 1992 to Farrell for “Bis-platinum complexes as chemotherapeutic agents.”
U.S. Pat. No. 5,380,897 issued Jan. 10, 1995 to Hoeschele, Qu and Farrell, for “Tri(platinum) complexes.”
U.S. Pat. No. 5,409,915 issued Apr. 25, 1995 to Farrell et al., for “Bis-platinum (IV) complexes as chemotherapeutic agents.”
U.S. Pat. No. 5,624,919 issued Apr. 29, 1997 to Farrell for “Trans-platinum (IV) complexes.”
U.S. Pat. No. 5,744,497 issued Apr. 28, 1998 to Valsecchi, et al., including Farrell, for “Trinuclear cationic platinum complexes having antitumor activity and pharmaceutical compositions containing them.”
U.S. Pat. No. 5,770,591 issued Jun. 23, 1998 to N. Farrell for “Bis-platinum complexes as chemotherapeutic agents.”
U.S. Pat. No. 6,001,872 issued Dec. 14, 1999 to N. Farrell, et al., for “Water soluble transplatinum complexes with anti-cancer activity and method of using same.”
U.S. Pat. No. 6,011,166 issued Jan. 4, 2000 to Valsecchi et al., including Farrell, for “Trinuclear cationic platinum complexes having antitumor activity and pharmaceutical compositions containing them.”
U.S. Pat. No. 6,022,892 issued Feb. 8, 2000 to Farrell, et al., for “Bis-platinum complexes with polyamine ligands as antitumor agents.”
U.S. Pat. No. 6,060,616 issued May 9, 2000 to Farrell, et al., for “Bis-platinum complexes with polymethylene derivatives as ligands having antitumor activity.”
U.S. Pat. No. 6,113,934 issued Sep. 5, 2000 to Farrell, et al., for “Platinum complexes with anti-viral activity and method of using same.”
U.S. Pat. No. 6,313,333 issued Nov. 6, 2001 to Da Re, et al., including Farrell, for “Multinuclear cationic platinum complexes with antitumor activity.”
U.S. Pat. No. 6,350,740 issued Feb. 26, 2002 to N. Farrell, for “Transplatinum complexes as cytotoxic and anticancer agents.”
S. Radulovic, Z. Tesic and S. Manic, Curr. Med. Chem., 2002, 9, 1611.
Y. Najajreh, J. M. Perez, C. Navarro-Ranninger and D. Gibson, J. Med. Chem., 2002, 45, 5189.
J. Kasparkva, O. Novakova, V. Marini, Y. Najajreh, D. Gibson, J. M. Perez and V. Brabec, J. Biol. Chem., 2003, 278, 47516.
J. Kasparkova, V. Marini, Y. Najajreh, D. Gibson and V. Brabec, Biochemistry, 2003, 42, 6312.
E. S. F. Ma, W. D. Bates, A. Edmunds, L. R. Kelland, T. Fojo and N. Farrell, J. Med. Chem., 2005, 48, 5651.
U.S. Pat. No. 6,867,316 issued Mar. 15, 2005 to Sohn, et al., for “Platinum (II) complexes of N-substituted amino dicarboxylates and the preparation method thereof.”
U.S. Pat. Application No. 20050090478 published Apr. 28, 2005 by Barenholz, et al., for “Platinum complexes and their use in cancer treatment.”
S. Zutphen, E. Pantoja, R. Soriano, C. Soro, D. Tooke, A. Spek, H. Dulk, J. Brouwer, J. Reedijk, “New antitumour active platinum compounds containing carboxylate ligands in trans geometry: synthesis, crystal structure and biological activity, Dalton Trans., 2006, 1020-1023, DOI: 10.1039/b512357g (web-published Dec. 7, 2005).